Penn Medicine experts in oncology, medical oncology, radiation oncology, surgical oncology, and more discuss clinical trials, treatment updates, and the future of caring for sarcoma patients.
Related Links: @PennMDForum Dr. Weber’s physician profile Dr. Maki’s physician profile Dr. Shabason’s physician profile Dr. Karakousis’ physician profile
Mhm. Okay we'll get started. This is welcome to the Pen CMi event related to sarcoma management. This is going to be about local treatment, clinical trials and the future of sarcoma. I'm Christy Webber. I'm an orthopedic oncologist and will be moderating this symposium today. I direct the sarcoma program at penn and I'll be working with dr robert Mackey and Medical oncology. Dr Jacob Sabiston and radiation oncology and dr yorgos carrot juices in surgical oncology. We hope to bring you um an overview and leave time for questions that you might have about this rare disease. The learning objectives have been sent to you previously. I just want to mention that this event will allow one hour of CMI. These are the disclosures of relevant financial relationships of the panelists and just to know you you will get an email within a week, not right away, but within a week um related instructions about how to claim your CMi after you fill out an evaluation. So let's get started. I'm going to give a little bit of an overview and then move into treatment of extremity sarcoma. Again, I'm Christy Webber. The phone number on the screen. If you have questions about the program in general, uh feel free to use that number also, if you're interested in coordinating care between multiple services, we can help with that for patients that need to see multiple providers. This is the new pavilion down at Penn and University City. This is a state of the art hospital that will house oncology patients opening at the end of october. We're very proud of the Abramson Cancer Center and the collaborative nature between clinicians and scientists. As you see on the bottom screen now, President biden started here several years ago with his Moonshot Initiative for cancer related care. You can see him with Amy Gutmann, the President University and next to her carl june was a leader in immunotherapy and we'll hear more about immunotherapy for sarcoma. With DR Mackey's presentation. The American Cancer Society estimates for this year show that there'll be nearly two million new diagnoses of cancer. But look at the uh numbers of bone and soft tissue cancer is only around 16 or 17,000. We're talking about a very rare disease and one in which it's important to have an experienced team. This is just a uh an overview of some of the clinicians, Certainly not all involved in the sarcoma clinical program at Penn. We have multiple types of surgeons, orthopedic oncology, surgical oncology, neurosurgery, plastic surgery. We have medical oncology next door. There's chop, radiation oncology and critical um Our experience, musculoskeletal pathologists and radiologists because diagnosis isn't key to treatment. All of these different providers have equal roles to play in the treatment of patients with these rare bone and soft tissue tumors. We're also extremely proud of our sarcoma science team. This is a really one of the places in the region that has a commitment to science. So these are NIH funded investigators at chop at Penn vet and at Penn Med that collaborate together working on various aspects of sarcoma with multiple mouse models. Remember that our primary goal with sarcoma, these are youngsters on this slide, but as to cure the patient. So we have the opportunity with a primary disease to be able to use multidisciplinary care to to achieve a long term cure as different than patients that we treat with metastases from um person Omagh's. So a few key points uh for referring providers, the multidisciplinary clinical care, really, we have expertise in all areas and it does amount to hundreds of hours of collective accumulative experience and training. We have easy access to appointments um uh either individually through the providers on the call or coordinated care through the number you see. Um the folks on the, on the webinar today all see patients in the same clinic and frequently on the same day. So it's very easy to get coordinated care. We have a weekly multidisciplinary sarcoma conference with radiology and pathology presence. Uh We frequently have uh pretty much always have same day radiology results. Um We can get same day image guided needle biopsies if we have the appropriate imaging available. Our pathology results are expedited. Um You're going to hear today about unique clinical trials related to radiation and systemic therapy and of course we're taking special care with safety during Covid, as I mentioned, the sarcoma research program here with NIH funding. We have tissue banking, both pre treatment and post resection. We focus on novel animal models using mouse and dogs, which are not just models, but also pets at the vet school metastases and the immune environment. And again, the collaborations are really critical. We'll move into my area which is extremity sarcoma if we talk about bones again, remember in the vast scheme of things, the most destructive bone lesions and adults are metastases followed by myeloma and lymphoma. Sarcoma czar much further down the line in terms of prevalence. Most common adult bone sarcoma is Condra sarcoma. And right now that's for the most part of surgery only disease. We just don't have great yet um systemic therapies for that disease. Uh and and it's less radiation sensitive. So um in addition osteosarcoma, post radiation sarcoma. We have we don't have our neurosurgeons on the call today, but we have expert uh neurosurgical surgeons here related to chordoma at the base of the skull and throughout the mobile spine. And sacrum ewing sarcoma. And I put in giant cell tumor because we do treat that in a multidisciplinary fashion as well. Remember that bone tumors generally cause pain. Patients are gonna they're gonna mention that they have pain but it can be referred. We often see patients to have multiple spine workups but the lesions in the pelvis have to think about referred pain. X rays are great to start, especially the extremities. And then we can always get an MRI scan with contrast a defined the lesion if needed. I'm not going to take you through an exhaustive surgical case list. But just a few examples of the recent standard of care. This is a patient with treated osteosarcoma. In the distal femur, you can see the lesion near the knee joint. And really the standard of care now is to replace the respect and replace that segment with a durable metal prosthesis that allows patients to get up and walk on the next day. These last anywhere from 10 to 22 beyond in terms of years before needing a revision. And it does allow that patient to get up and get back to some semblance of normal life If it's a sarcoma that's away from the joint um in the bone, we can often save the joint, especially in a young person like this 18 year old with Osteosarcoma. We can respect the area, replace it with a cadaver bone. Sometimes add in vascular is bone from a fibula graft on the same patient and be able to get that could ever go to hell and leave the patient with a normal knee joint that will last you know long term. This line is just an example to show you the type of coordinated surgical care we have here at Penn. This is a recent patient, 49 year old woman who had a large, extremely large Congress Sarcoma, the pelvis involving multiple organs and the hip joint. She had a team involved six surgical services Ortho urology, Julian on colorectal, vascular and plastic surgery to be able to respect this with a margin free resection, the patient's doing well. This is an example where we collaborate with our neurosurgery colleagues. This is an older patient with Congress sarcoma extending through the lumbar sacral spine and into the pelvis requiring resection of multiple nerve roots in a limb sparing resection with reconstruction using hardware vascular sized fibula graphs to reconstruct the pelvic ring. Uh and she's seven years disease free and able to ambulance it. Um with this type of reconstruction, we move into soft tissue sarcoma much more common than bone but still rare. The complicated factories. So many different histological subtypes. And you'll hear more about this later. Um Oftentimes we'll treat them the same, but hopefully in the future will have unique neo adjuvant options for each of these histological subtypes. So the problem with um soft tissue sarcoma is his patients often arrive late and the faint. It can be predetermined depending on the size and the grade of the sarcoma. I often see patients who have had the wrong operation based on the wrong presumed diagnosis. So not again, not to go into an exhaustive review, but just the critical piece today is if you have a patient with a soft tissue mass, especially one that's growing or one that is, you know, more than a few centimeters in size. It's important to get an image. There's really not a lot of role for Rhys acting. Things with no image. So based on an MRI scan of a soft tissue mass, if it's a determinant lesion, like a lymphoma or ganglion cyst. Yes, it can be removed without a biopsy, but most things are indeterminate. We can't be 100% sure what they are and therefore they need a biopsy before we move forward with surgery. I see patients every week in clinic who have had a surgery um based on on an inaccurate diagnosis and then a sarcoma has been removed in a way that perhaps was not ideal. This is just an example of the lymphoma. Not to overstate the point. This is a lie poma and you see the lipo metis features that look the same as normal fat on every sequence including the fat SAT sequences. This does not need a biopsy. However, this even though it is white on the screen, it is not the same as fat and the surrounding area. This is not determine that this is not a lie poem and it requires a biopsy. This is an example of a patient with a high grade round cell lipo sarcoma. These patients generally have chemotherapy Initially this patient also had preoperative radiation, which is a mainstay of local control. You can see the tumor has retracted away from the underlying femur and allowed limb sparing resection with negative margins and high necrosis. Finally, soft tissue extraction with our plastic surgery colleagues is critical. Um We often have patients who have a defect in the extremity in a radiated bed. Uh wound complications are higher in those situations and so local rotational or free flaps not only prevent breakdown, but in this case of a patient who had a sarcoma involving the biceps muscle and tendon had a rotated lattice imus flap to not only fill the space but reconstruct the biceps tendon. Local control with extremity surgery is about eight in patients who receive radiation and surgery. And this is data from Sloan Kettering when you're talking about the rich prepared meal area. However, and Yorgos is going to talk more about this. The local currency rate can be up to 50 depending on the type and extent of the sarcoma, given the difficulty in obtaining local control in that environment and I'll end there. This is just our steps to cure sarcoma event that we have every spring. This is our patients and our our doctors and scientists come out in force uh to celebrate mobility um uh with with patients in there. So we're super proud of the program and with that I'm going to stop sharing my screen and introduce dr carrick uses who's going to talk to us uh in addition about more surgery for sarcoma focusing on the retro peritoneum. Thanks for being here today. Mm hmm. Thank you. Christi. Can everyone see the slides? Okay. Right. So, um, For the next 10 minutes or so, I'd like to talk to a little bit about the way we treat Sarcoma is that are in the abdomen or in the retro peritoneum. And the unique challenges that these types of tumors can provide. So as we already heard, Sarcoma as a whole are very rare tumors that account for less than one of solemn malignancies and retro perinatal tumors are even rare, accounting for about 10-20 of Sarcomas by location. Most commonly they present in the 5th or 6th executive life And like extremity Sarcomas and other locations or multiple histological subtypes over 50 it's logic subtypes that can be seen most commonly these are likely sarcoma, uh, what is now called ups or playing more folks are comas and limewire sarcomas frequently these tumors present late or discovered incidentally. And this is an important point when we talk about sarcoma is because of the challenges that that can create. Unlike carcinomas, sarcomas can often be displacing in asia, pushing organs and other tissue aside. As a result, they can often be asymptomatic until they're quite large. Occasionally, patients may present with GI or your federal obstructive symptoms, but oftentimes it's just increase abdominal girth or palpable abdominal mass that patients will present with. So certainly if you have a patient with a new mass of the abdomen, they should be referred for for imaging. And the imaging can either be CT scan or MRI the abdomen pelvis that that will allow us to see the anatomical relationships of these tumors to other important structures. And also typically cT imaging of the chest where these tumors can oftentimes spread to many times. A C. T. Scan can differentiate between a sarcoma and other types of retro perennial to us or metastatic lymph monopoly, but many times that may not be clear. And so it's certainly important to consider a differential diagnosis when when everyone has an inter abdominal or intracranial mass. And on this differential include things like lymphoma, large lymph node conglomerates. Uh in one instance, I had a patient actually with metastatic lymph antipathy from testicular origin that presented is what seemingly was a retro critical mass. Certainly other organs in the retro peritoneum of the pancreas, kidney or adrenal glands can present as retrofitting the Alzheimer's. Um, and so should be carefully evaluated. Clinical signs and symptoms can sometimes help you distinguish ideologies, but oftentimes it's not possible. So whether to buy ups here not these masses, oftentimes is a, is a question that was controversial I think probably less so now. Uh, there was a theoretical concern I think early on about seating in the peritoneum of these masses with biopsy, but I think data is really born out that that's not really the case. Uh, and so in cases where the imaging is pathan demonic for particular histological diagnosis, like for lipo sarcoma is biopsy may not be essential, but for other instances it may be very important to guide multi modality therapy and also affect the type of operation One will do like in the extremity, important prognostic factors for retro peritoneal us include things like age, grade histological subtype is incredibly important in terms of predicting likelihood of recurrence from these to us and size and oftentimes as I mentioned, these are present by the large size and recurrence rates. If you take them, take these to us as a whole. As we already heard, Can be on the order about 40-50%. And that's primarily dictated by the recurrence rates of like Oh Sarcomas, which are the most common histological subtype for retro Pernille sarcoma surgery is really the mainstay of treatment for these to us and we aim to try to get a complete resection of these tumors with margin negative resection frequently. This involves on block resection of continuously involved organs, most commonly kidney colon, distal pancreas and spleen. But oftentimes there may be other organs are removed, including vascular structures. Other modalities also can be important in treating these tumors, including radiation therapy and systemic therapies. And we'll hear more about that in the next couple of talks. I just want to highlight a recent trial that looked at the impact of radiation therapy for radiation for retro perennial sarcomas. Uh This was a randomized trial from europe that randomized patients uh that to neo adjuvant radiation prior to resection of retro perennial sarcomas. And this trial uh albeit was a negative trial. Do not see a difference between patients who did and didn't get radiation therapy. There was a suggestion though, of of improved outcomes and patients with retro peritoneal lipo sarcoma specifically. And so we we routinely discussed these cases for consideration of preoperative radiation and make these decisions on a case by case basis. So again, without going too much into details, I wanted to just highlight some examples of surgeries that right to perennials are comas. Um, and this is a case of a 55 year old male with increasing abdominal girth for a couple of years prior to finally obtaining a CT scan. And we can see is a large mass and the retro peritoneum that's displacing the colon all the way just below the abdominal wall and reach quite a large size. This patient actually presented to the clinic with shortness of breath because of the compression of the diaphragm by this large mass. So these tumors can can present unique challenges just by virtue of their various size uh and and involvement of intra donald structures. This was removed on block with the right kidney uh and wait a total of £40. This patients followed for several years Without evidence of recurrence. This ended up being a de differentiated lipo Sarcoma 48 cm. Another patient, actually a 35 year old present, presented with pelvic mass and actually presented with complaints of urinary retention and cross sectional imaging demonstrated a 17 centimeter mass involved the prostate and seminal vesicles and also with compression of the right ureter, causing also right hydro necrosis, also involving the bladder base. And this was removed in conjunction with the urologic services, highlighting again what DR Webber mentioned, which is this multi disciplinary surgical care? This tumor is removed on block with the prostate and bladder and an illegal conduct diversion was performed and this proved to be a malignant, solitary fibrous um 23 cm with margin negative resection. This patient unfortunately succumbed to lung metastases um within a year but maintained local regional control in the abdomen. Another patient was 36 year old female with a history of hereditary exhaust oh sis, who presented with a large abdominal mass that was consistent with a large contra sarcoma. And this really extended all the way from her diaphragm down to her pelvis as a 33 centimeter mask really occupied her whole abdomen. We discussed this case very carefully in our multidisciplinary clinic and actually this was removed in conjunction with our neurosurgical team and our orthopedic surgical oncology team uh in a stage fashion uh first by removing it off of the spinal um column and severing the nerve roots in a clean fashion to prevent a CSF leak. The lamb anatomy of L. One through all three and subsequently taken from an anterior approach to remove the tumor that extended again all the way from her liver down to pelvis. And this proved to be a 36 centimeter high grade de differentiated contra sarcoma Weighing about eight kg. This is a very rare case of sarcoma of a 75 year old male presented with likes falling after a boating accident. Um and imaging demonstrated what was initially felt at an outside hospital to be a thrombosis in the inferior vena cava. But M. R. I. Showed uh the lesion was enhancing uh and was therefore felt to reflect a neo plasm. This in fact turned out to be an I. V. C. Lamar sarcoma. These are extremely rare tumors for which we have a particular experience in managing here at penn. Uh And these tumors can present unique challenges because of their vascular involvement. This patients was placed on vino vino bypass shunting blood from the legs to to the head. Uh an upper body while the vena cava was clamped. And the tumor is resected on block with the right kidney because the extension of the tumor into the right renal vein and the vena cava was reconstructed in conjunction with our vascular colleagues with a home a graft. And this again was a 4.3 centim high grade glamour sarcoma. These tumors really can can occur anywhere up and down the length of the I. V. C. Down to the iliac vessels and also in the renal vessels as well. So as I hope I highlighted through these cases really these these are complex tumors that can provide unique challenges but can be handled by by a multidisciplinary team. Oftentimes requiring multi modality therapy with radiation and or systemic therapies but even surgically requiring a multidisciplinary team of orthopedic oncologist, surgical oncologist, neurosurgeons, vascular surgeons, plastic surgeons and even the peri operative care entropy by our anesthesiologist. Profusion ist and post up are really important ensuring getting these patients through these procedures safely. So with that I'll end and uh I'll introduce dr Shavelson from radiation oncology will talk to us about the role of radiation in sarcoma. Thanks service morning everyone. Um Thanks for logging in this morning. Um some Jacob Davisson, radio psychologist here and excited to talk to you about the role of radiotherapy for soft tissue malignancies. Um I'm primarily going to be focusing on soft tissue sarcoma even though we do play a role in bone sarcoma. So as you can see from the slide, radiation does play an important role in multiple areas for soft tissue malignancies are primary role is in conjunction with surgery in the new edge of an argument sending for extremity or trunks are comas but really it is standard of care to incorporate it into limb sparing surgery for Really any stage two or 3 uh sarcoma and you know some select stage ones as you can see in the N. C. C. N. Guidelines to the right but we also play an important role in un respectable disease for more durable local control um As well as an increasing role with potential durable local control with all ago metastatic disease with techniques such as S. P. R. T. Which is more than a blade of therapy and I'll talk about that a little later as well as in palley ation of metastatic disease. Um And as dr carcasses alluded to the role of radio therapy and retro peritoneal sarcomas despite a randomized trial remains controversial. Um If it's going to be used it should be in the new age of in setting. And really only a role in select light posts are comas. Very limited role in my oh my oh sarcoma I didn't go to next line. So the you know radiation was established as part of the standard of care for extremely sarcoma is back a few decades ago. Were previously the standard was amputation. And I always like to highlight this trial because it was really spearheaded by my mentor and dear friend Dr Gladstein at the N. C. I. Where they you know perform this small trial. Looking at amputation versus limb sparing surgery plus radiation. And they showed you know very acceptable local control rates while able to spare the limb no difference in disease for your overall survival. So this established radiation plus limb sparing surgery as a standard option. Next slide please. And this was logically followed up by a trial looking at is radiation needed in addition to limb sparing surgery And again at the N. C. I. They were able to show that certainly yes there is a definite improvement and local control when you add radiation no improvement in survival. It was not powered for this study for this for this endpoint. And we typically don't think as radiation is improving survival. But if you do look at large national database studies, there may be some advantage in terms of overall survival, excitement. Um so, you know, despite the fact that radiation really is standard of care for extremity sarcomas, we looked at this as a kind of a national uh national patterns of care level across the nation. And we're pretty shocked and disappointed to see that about 40% of patients Who with stage two or 3 Sarcoma who in most instances should require radiation. We're not and this line is pretty flat over the last, You know, 15 years or so, so not really increasing. So this is a bit disappointing to see. Um and certainly, you know, further education is needed. Um uh next slide please. And, you know, I mentioned at the beginning that radiation can be, you know, is very important in conjunction with surgery and can be delivered either pre operatively in the neo. Adjuvant setting or adjuvant setting. Uh And there's advantages and disadvantages to both. We and most groups tend to favor the neo as of an approach and that's for a variety of reasons which I highlight here on the slide. First of all can get away with a lower dose of radiation. 50 gray in 25 fractions versus 60 to 66 32 33 usually treating a smaller volume. You know, you have a gross target as opposed to a larger operative bed. The disadvantage of neurons radiation is there's a higher rate of wound healing complications, but those are often reversible, whereas the complications for the higher dose of radiation in the abdomen setting and larger volume are typically irreversible. And those are late side effects such as fibrosis, Idema stiffness. So this was evaluated in a large randomized trial Showing these differences in toxicity with really no difference in cancer control outcomes with about 90 local control and equivalent disease free and overall survival. So it's really about toxicity and pretty much in almost every case we prefer new regiment radiation next site. Um and again despite these benefits, we still see that preoperative radiation is underutilized across the country. There has been an uptick since that trial was published, but still only 30-40 of patients who are receiving radiation with surgery are getting it in the new achievements setting despite certain definite improvements in patient morbidity from this approach. Next slide please. So also, you know, the technique of radiation certainly matters. Um We tend to favor using a technique called intensity modulated radiation therapy, also known as I. M. R. T. Um This is kind of a more advanced form of radiation compared to the historical three deacon formal where you allows us to better spare um certain structures such as the nearby skin bone and other soft tissue, which certainly has improvements in some of the toxicity outcomes. And this slide here just highlights uh you know, four or three important trial starting from the right is the postoperative arm from that trial, I alluded to comparing preoperative and postoperative radiation and then going to the left. Um you know, the preoperative arm of that trial. And then two more modern trials primarily using MRT. And you can see that there is certainly less late toxicity in the form of fibrosis stiffness and Oedema. As you move to a more of approach with the MRT, where we see it really in less than 10% of patients. Disappointingly though, we actually don't see much difference in wound toxicity where that consistently is about a third of patients across trials to get preoperative radiation. Even with I. M. R. T. Will develop some wounds wound healing issues. Although there's there were some issues on how the I guess the iron marty was designed. Um There's been limited studies on proton therapy but next slide please, you know, one of the advantages um uh Pen is that we do have a proton therapy available. This is a unique form of radiation um where the primary advantages in the physical properties of how it's delivered where there's mass two protons so they actually stopped. So there's really no exit dose. Um And this primarily although admittedly not routinely used for most of our patients with extremity star comas. Um It does play an important role in young patients. We do see a lot of patients in the A. Y. A. Population where there's benefit reducing the kind of overall radiation exposure. Which could theoretically reduce a secondary malignancy risk down the line. In addition retro peritoneal sarcoma. There's certainly a benefit with a reduced dose to bow liver kidney. We see although very rare some cardiac sarcoma is here and protons certainly help us allow us to does escalate in those patients and also in the setting of re radiation and either locally recurrent sarcoma or in patients who unfortunately developed a radiation induced sarcoma from other therapies. Um And here just below is a case example of a patient with a retro peritoneal sarcoma was actually under a sectoral comparing an I. M. R. T. Or format plan on the left versus a proton plan on the right and you can see basically almost no dose to the nearby bow. So certainly in in select patients advantage. Next slide please. In addition, over the last number of years we've been using S. P. R. T. Scare tactic, body radiotherapy uh more frequently. Um This is a technique where we use high doses of radiation in you know essentially 1 to 5 fractions and it's thought to be more of a plate of dose. Um this allows us to get more durable local control in um you know primarily Allah go metastatic disease. Um there's been numerous retrospective studies in Sarcoma showing excellent local control with this approach about 90 primarily in lung metastases but also another such a spine and soft tissue. Um And this approach will become even more and more important as hopefully you know as the years go by and we improve systemic options to have this as an option to help a plate potential Olivo progressive calico metastatic disease. And below are just two case examples. On the bottom left is a patient with a C. Spine, My task deceased that we're able to treat to 30 grey and three fractions. And as you can see here with this technique, you can kind of create this nice, you know, avoidance region or doughnut around the spinal cord. And then on the left is a patient who had oligarch metastatic disease with four lung metastases. All were treated concurrently with S. P. R. T. Um Next slide please. In addition from the kind of more investigational end over the last number of years, there has been increasing interest that radiation may impact the anticancer immune response and leach and essentially enhance it by multiple mechanisms potentially into mediagenic cell death, increase tumor antigens and allow immune cells to better going into the tumor. Although still investigational. There's lots of clinical trials across numerous disease sites investigating this topic And now, fortunately including in sarcoma next slide. And this is reflected in a trial we have open here. It's a stark sponsored trial, multi institutional where it's actually randomizing patients in the upfront setting with the localized disease to either standard of care, preoperative radiation followed by surgery or in cooper incorporating federalism into that approach. It's randomized with the primary endpoint is disease free survival. Um to hopefully, you know, uh lower the risk of metastatic disease. It's limited in the histology based on uh data in the metastatic setting where primarily immunotherapy or pd one directed therapy was more affected in the U. P. S. Population and like Los Arcos population. Um So we're excited to see the results of these uh this trial. I believe it's nearing end of a cruel um next light. Uh I just like to end with some kind of new exciting developments in the fields in the field of radiation oncology for sarcoma. Um One you know um promising approach is hypo fraction radiation therapy for patients getting new arrangement radiation and extremity sarcomas. Where The goal is to reduce the amount of fractions from the standard 50 grain 25 fractions To about five fractions and the most common approaches 30 grey and five fractions. This is a biologically equivalent dose. But when we shorten the course of radiation with a higher dose per fraction, there is a concern for worsening late toxicity. Um this has been investigated in a lot of single institutional experiences and trials with apparent similar local control and toxicity, but the follow up is not quite as robust as you know with our more standard fraction nation. So still investigational but a lot of centers are using it as standard of care and I think in the future it will move in that direction. Um In addition there's there's uh work to try to actually reduce the dose of radiation. And this has primarily been shown in a histology of mixed lipo sarcoma which is probably the most radio sensitive of the sarcoma histology is and really the only one that that regresses pretty much while we treat you can get significant regression with radiation. And just this year there was a randomized a single arm phase two trial which reduced the dose from 50 to 36 Grey all in standard fraction nation. And very Encouragingly that there was 100 local control is about 70 patients I believe. And the wound complications were low about 17%. Which is equivalent to what you would expect in patients who have not had neo adjuvant radiation. So these are exciting approaches to see how we could improve both outcomes, as well as morbidity, oncological outcomes and morbidity for our patients. Um, So next slide. Um, so just you know, please reach out always happy to discuss cases or you know, whatever it is. However, we can help. So thank you so much for logging in this morning and looking, going to chatting more Jacob. All right. Dr Maki can bring it home here. Absolutely. And here's the second fellows on the listening end of the webinar, just thinking about some questions. Got some questions coming in already, but um we'll have plenty of time to answer any questions after DR Mackey's talk. All right. This section of talk, we'll talk a little bit about systemic therapy for these chambers. Especially things are getting more complicated as we begin to integrate genomics uh, into the treatment plant. It's really helping us with the diagnosis as well and therefore helping us choose therapies overall. Um, it's got more and more complicated over time taking care of these tumors. The most recent bicycle, the so called WTHR. Com, a blue book, 180 different benign and malignant diagnoses amongst the soft tissue and bone sarcomas. At least 50 of these are sarcomas, although there are a lot of these benign tumors as well. Kristie already touched on the idea that there are some tools that are locally aggressive. They don't metastasize. And it turns out that we have systemic therapies for all of these as well. That can help out, uh, in terms of the local regional management of these tumors, including tina, synovial, giant cell tumor, giant cell tumor, bone and uh, and geographic and you make Selma's, which sometimes occur in the pelvis for the around the orbit. Um, so really, I mean, it's really not highlighted today because we don't have our pathologist speaking, what is the proper diagnosis? We really need our pathologist to tell us what the truth is. Without that, we really can't help name our therapies at a patient appropriately. Um once we've cleared that hurdle, we ask whether patients should receive no agenda. Adjuvant therapy. New regiment therapy as you know, is being used in many, many different cancers. Now. Osteosarcoma back in the 1970s is one of the first examples where that was used. How does this therapy interface of radiation and surgery? Especially as we're talking about more neo adjuvant therapy for radiation as well than was given historically in the past? How do you have a chemotherapy to that as well? And what is the next line of therapy that we should consider for? Um a patient with a given histology who presents to us with the variety of complications from potentially other diagnoses. And of course our their clinical trials to think about for such patients. The big issue is is that we have a limited number of drugs, but nearly a limitless number of diagnoses. Um We have all of these soft tissue and bone subtypes. This is not an exhaustive list as you see there, but the new layer of complexity that's been added um are the fact that we now have a specific um molecular subtypes of these different tumors, and each one of those may behave at least somewhat differently from its cousin. Um And add to that things like metabolic reprogramming of the genetic changes that we see. And then in the number of tumor as well, we've got a lot of choices. And um each patient really is true and individually talk about some countries being rare. Um, each person really presents a unique set of challenges. Um, because of this overlay of rare diagnosis, complicated genetics, potentially. And the need to make a therapeutic good. I'm just popping in. This is Christy. Not seeing the slides advance. Can you shift that presentation mode? And yeah, we're still seeing the first slide only. So that's not good. Well, we're listening. So we're learning. That's good. Yeah. Uh huh. And they just did the matter of the window that I'm sharing them. How we doing there. Um, can we go to presentation mode and maybe go to your first slide? We're still in the double. We're in a split split mode. Uh, better. They're all right. Terrific. Going back to wherever you were. Yeah, exactly. Just with the graphic, basically the limited number of treatments that we have to offer people. And uh complicated issue with regarding all these different 50s are common diagnoses or more over laid with the molecular character characteristics of each summer metabolic issues at the genetic changes. It's a complicated scenario that's for sure. Um, one of the good stories hasn't been mentioned so far has to do with gastrointestinal stromal tumor. Just um, we're really at the point now where we have essentially complete first past genomics analyses of this of these tumors. Um, as you well know, uh frequently kit is the gene most commonly mutated and just with implications with imatinib and other therapeutics for this diagnosis. PdF receptor alpha is the next most commonly mutated tumor um in this diagnosis. But now we've been able to sort out really through the so called triple and quadruple negative, just that each one of them, especially through uh panel sequencing and transportation analysis of a few of those tumors. We've really been able to nail down the genomics of all these tumors And that really becomes an issue of uh what do we do for metastatic disease? Three years of I'm at nib in the abdomen setting is appropriate treatment for high risk Gastrointestinal stromal tumors. But now for metastatic disease. Uh we now have a series of agents which are available. Five drugs are now approved just a couple in the past year to 18 months or so, which give us new options. And some of these are being tested uh to try and replace and supplant second line therapy with the Senate for example. So those trials go on as do novel therapeutics. But this is really one of the great examples of hand and glove mutation driver which drives a cancer and that we have a therapeutic or group of therapeutics that are focused on and can certainly help in terms of management. This is a great multidisciplinary disease as well. There's a lot when you have a large let's say electric project mass. That turns out to be a just we'd like to give neo adjuvant therapy and anticipation of surgery. And then oftentimes we'll continue that adjuvant therapy after surgery. The baseline question we really have to ask any new patient who comes to our office are retreating them with curative intent or palliative intent. And um do we treat them with curative intent with either chemotherapy before after surgery? Uh, palliative intent. How do we treat their metastatic disease? Both were standard agents. And how do we integrate clinical trials that are available? Imagine therapy depends on the diagnosis. We already talked about. Just the other key place where we give adjuvant chemotherapy is for pediatric sarcomas. Um, all those diagnoses that are more common in Children. Ewing sarcoma, rob thomas, sarcoma and osteosarcoma when they occur in adults. We like to pattern the therapy based on what our pediatric oncology colleagues give. Um it's not always possible to give the same intensity of therapy, but we certainly do try and match as much as possible what they are doing and uh beyond that. Uh so their so called other garden variety sarcomas, undifferentiated polymorphic sarcoma, extremity lai mao sarcomas and so forth. The data are quite a bit less clear. Uh meta data analysis does support it's used by and large and if you're you're giving it just like Jacob was saying with the new regimen radiation therapy, it's probably better given in the neo adjuvant setting. Um Then after surgery, after the cells have had another chance to divide a couple of times by the time they see their first chemotherapy, What is the best first line treatment for metastatic Sarcoma you can imagine with all of those 50 different diagnoses um that that might vary and um uh in essence, if you have somebody who really needs a response, we try and give combination therapy um if it's lower volume disease and you're a little bit more concerned about quality of life, there have not been a lot of studies showing evidence of synergy and oftentimes you can give sequential single agents. The other thing we have to consider in terms of the drugs we choose are the specific astrology because there definitely is a sensitivity and resistance pattern for each subtype for drugs. And some of those examples are are shown below. Perhaps one of the best examples or angio sarcomas which are pretty much the only sarcoma to respond to tax seems as a single agent. Um Whereas I Foster might, it turns out that just doesn't work as well for those, at least as some of those other agents as they are available. Some of the systemic therapy clinical trials were conducting with the heart in there. Um and marc diamond at pennsylvania Hospital. Uh study that is just about to open for unemployed us as an intensive therapy. Looking at Cabazon to niB is sort of a is open iB plus a sort of agent with or without feeling the mob and the volume of the classic drug therapy for melanoma. Uh This is a randomized phase to design with crossover with some translational research endpoints. Uh This is actually being run out of uh Washington ST louis. Uh And we're participating in that particular trial their commercial trials as well, such as the so called Envious arc Study looking at their PD one inhibitor for metastatic undifferentiated Sarcoma, specifically as Yorgos mentioned, it's one of the histology is that responds two P. D. One inhibition relatively uh consistently and also MbM two inhibitors with a P. D. One inhibitor, there's an industrial child for that. MgM to amplification is very common in those de differentiated lipo sarcomas and um that remains a difficult since they keep recurring. There are a limited number of surgeries that can be done. We have very limited success with the chemotherapy drugs we normally given. So we need new ideas like this MGM to inhibition uh to try and further uh the outcomes for our patients. We're interested in opening and working on the process of opening. Ewing sarcoma studies with Patrick Gohar over a chop the dark 37 study is one example of that drug called Urbanek Did in which he showed in the laboratory was effective in Ewing sarcoma that's being rolled out as a phase 12 trial as we speak and development. Also for just, we're looking at a ct 40 antagonism with Ron di matteo um our Chief of surgery who has an interest in that particular diagnosis. So um we have our our standard uh therapeutics for sarcoma surgery, radiation and systemic therapy. We're trying to degrade those together, but now we're looking to incorporate, of course kindness, targeted therapy, metabolic and epigenetic therapy as well as of course immunotherapy towards the betterment of outcomes of patients. You've seen a couple of examples in terms of trials, dr Shavelson and uh just showing you ways of trying to do that. So at the end of the day we really do need to get the diagnosis right. We need expert pathology review um increasingly using new adjuvant therapy, just like other cancers and for metastatic disease treatment is increasingly a function of that primary diagnosis. And again forces us to be um darn sure what we're treating before we treated and and we're trying to incorporate those genetic markers, genomic markers um into the river plans for people as they come along. So we're trying to act at the patient level. But working with our colleagues both here at penn across the nation and in fact worldwide on some of these trials for collaborative diagnosis specific trials and with that, I will stop and of course, welcome questions at any time and I think we'll have our discussion section now, Kristie, is that correct? Yeah. Go ahead and take your screen share off again. That sounds pretty well. Thanks everybody. Um we've got, you know, 10 minutes or so for questions so feel free as those in the audience to type in questions to the Q. And a. And I've got a few to start with. There's one question about focusing on the specifics of new edge of treatment to high grade sarcoma is that came in before bob's talk. So I think we talked about that a little bit. You know, it is histology um and co morbidity dependent patient AIDS etcetera, related to the systemic treatment. But all high grade sarcomas essentially get preoperative radiation and surgery. Um I know for myself, at least on the extremity sarcomas, I wait 3 to 4 weeks after the completion of radiation to do the surgical resection Yorgos. What if you have a patient with radiation being used prior to surgery? Um What's the time frame? Is it different in the retro peritoneum? Would you wait a longer time, A shorter time? No thanks Christina. Typical time frame I think as you used in the extremity about four weeks. Uh and we really haven't seen a significant increase in morbidity and complications when administered in that time frame. Um Of course in the record premium as we discussed, we use it selectively depending on the histology ease. But when you're in the restaurant name, do you wait longer than four weeks or or as four weeks around the same timeframe? four weeks? I think it is about the right time frame. Okay, great. Um Jacob there was a question about S. P. R. T. And the use of uh of it in lung metastases from sarcoma. You touched on that in your talk? Uh Do you have comparative numbers related to surgical resection versus S. BRT for lung metastases? Obviously, some of these patients are older, they do have comorbidities. They may opt for a less invasive option. Um Is it critical to biopsy the lung nodule first to make sure you have the right diagnosis? Or can you talk a little bit more about that that touched that that that inflection point between surgery and radiation for lung mets. Yeah. So I mean I think I guess the first off the biopsy depends on the clinical situation how safe the biopsy is. Also you know this is the first sight of metastatic disease and it's a single lesion then you know certainly biopsies appropriate or just you know have a menace detected me to have it taken out and um which are are certainly appropriate. But in certain instances we can treat without biopsy if it's pretty definitive that it's metastatic disease. You know. S. P. R. T. Vs. Surgery. I I view them as a pretty equivalent and local control. I mean with S. P. R. T. We're getting close to 90% local control. It's hard to get much better than that. And in the end you know that still the primary problem is controlling the burden of metastatic disease. So in my mind you know we certainly have a multidisciplinary discussion have thoracic surgery way in um or us to treat. But um in my mind both pretty equivalent for for their goal of you know hopefully eradicating that tumor. Um And again sometimes you know if it's three sites on both lungs we could still do that with S. P. R. T. But doing you know three hungry sections although doable maybe you know more and more of it. And again in the older patient surgery just made you too. There's a question about um late effects both of radiation. Late effects specifically development of secondary cancers and also late effects of chemotherapy. So you have a sense of what the prevalence is of that. Either bob or Jacob development of procreation, sarcomas, leukemias from chemotherapy. Yeah. I mean uh if you wanna go first uh for radiation, you know, it's it's extremely rare and something, you know, we think about a lot with younger patients. Um but you know, it's still very rare, you know, typically about some 1%. Um We have a little skewed view because we do see, I mean one of the primary tumors, you see that's radiation induces sarcoma. So we see a fair number of radiation and sarcoma is here from a variety of different um you know, initial cancer diagnoses. So we have a bit of a skewed view but you know, although we stress that it's a possibility. It's very low and you know, still have to treat the primary two of our. So it's there it's low it's something we more worried more about with younger patients a y A population. Yeah. And uh I mean, they're good data from studying pediatric patients who've gotten radiation over time. Yes. That the risk does go up over time. That's really why we don't like, for example, some of these diagnoses Desmond, you are, you can radiate those. Um but since we have other modalities to use for that diagnosis, since it doesn't metastasize, since oftentimes will happen in somebody who's younger and their, let's say their their thirties, um they would have to live with that radiation for a long time. So, in our discussions in tumor board, for example, we're trying to figure out other things we can do to help mitigate the timber without using radiation, right? Yeah. Uh and and deal with an interventional radiology techniques and so forth for those as well in terms of chemotherapy. Um, we've had perhaps the biggest problem for people who get longer courses of anthrax cycling's or my foster. Hmeid calculating ancient based therapy for for a year, that sort of thing. Or if they're on treatment for a long time they can develop. Mds. It's fortunately. Um, we're also the uncommon side effects of treatment of um over the last 25 years I think of likely cause leukemia. Um perhaps in conjunction with the RT sometimes will give we give sandwiches of anti cycling's and um and radiation more in the past and then we do now. Um. Um, but two or three times in my career, um the anti cycling and uh took four summers to based ones, the topside based tumors typically will occur within about a year or so of therapy. Whereas those that occur and associated with calculating agents are more commonly seen more on the kind of the 3 to 5 years range after, after chemotherapy has been given and often times they go through an M. D. S. Space before they developed leukemia. But unfortunately uh well something uncommon side effects even in our pediatric patients we've monitored for for a long time. Similarly for chemo toxicity, we worry about cardiac toxicity of course, perhaps more of an issue for younger patients. Um uh the we follow, ask your recommendations by and large, um saying you should use the cardiac protectant extras oxen starting at 300 mics per meter squared of dr. Benson or doctors an equivalent and often times for patients where we make could be concerned that doctor Robison may be the only drug that works for them. We can talk about even starting with psycho one with giving extras oxen. Um I think that's very much in play because with that sort of an approach, you can literally get to 1000 mixed per meter squared of dr percent or more just to play on that. What what how long do you follow people with labs after they've gotten chemotherapy just to be screening for that incredibly rare event? Is that routine thing or do do we just look for other symptoms? Yeah, we, by and large just uh follow them. They're going to get lab tests for other reasons. Oftentimes or remanded back to primary care. We still follow people for extremity sarcomas in some way, shape reform from an aesthetic disease. Even 10 or 15 years after their initial diagnosis and some of these tumors, you know, as you know, the ones you remember, those are the ones that have shown up even 20 or 25 years after their initial diagnosis. I'm not sure how it happens, but it still does. So we may revert from cat scans back to chest x rays for for uh monitoring for recurrence. But people are followed for a long time. But for lab tests not so much. We don't we don't have good tumor markers. For example, we don't have A P. S. A. Or a. C. A. We can follow like we can perhaps with circulating tumor DNA. Uh which is uh really being studied pretty intensively these days. Of course in many diagnoses. Maybe that will serve as a means to uh follow patients for their sarcomas as well if we if we identify the correct markers. Um The uh just a point about the complications the post radiation sarcoma, ironically we often when we see those, we actually treat them with preoperative radiation and surgical resection. In addition to consideration of chemotherapy. But patients with post radiation sarcoma do have a fairly poor prognosis have a high risk of metastases. Um I also want to mention, I didn't mention it my talk. But in the extremities, if if you have a patient who has received radiation and they have a surgical resection where the perry Ostrom is stripped off of the underlying own, generally a femur, we worry about a post radiation fracture. And if that happens, it's it's problematic because the bone doesn't have the ability to heal. So, utilizing a prophylactic stabilization of those bones if depending on the type of surgery and how much radiation people have gotten another nuance of care. Um There's a question about radiology reports um on the lipo type of tumors and I and I think this this hits home for for me, we often have patients referred to the clinic um with a concern for a liberal sarcoma. Um I'll focus on extremities and uh you know, just to be clear the um fatty tumors that don't have any high grade component on imaging. Um in the extremities there, they're not liberal sarcoma. Is there used to be a term called well differentiated lippo sarcoma that's referred now to the retro peritoneum. And it has a different biology and the different risk of recurrence when it's in the retro peritoneum. But in the extremities we call it a typical like poem are atypical lipo metis tumor, those are benign tumors. Um And so many patients get very nervous when the radiology reports as well differentiated or any type of life was sarcoma and extremity. So we we are often reassuring patients that those are benign lesions which they can either have removed or not. Um Again, different behavior in the extremity. Uh and the rectum perineum. Um um Again, Yorgos and Jacob, we talked about the trials that show that maybe radiation doesn't have a lot of effect in the neo adjuvant setting in rich parent Neil sarcoma is. What about the recurrent situation? You know, the recurrence rate is so high with rich perennial sarcoma. And so you have a recurrent disease, You know, four cm focus right near a critical organ. Um You know, you've already started that that problem where it's probably going to be more likely recurrent and recurrent and recurrent again. Is that an indication for radiation? And if so, is it pre or post operative radiation? Yeah, so thank you. Christine. I mean I get very nervous obviously when I see recurrences of sarcomas because you know, that usually signals a cascade of multiple recurrences. And so um you know, we obviously individualize it case by case basis, but for a small tender, medium sized tumor that's in a location near critical vascular structures rather an atomic considerations. I think radiation could be very helpful. Also, again, histology dependent, particularly if it's a like a sarcoma do different shit, like, oh sarcoma. Uh and and for me and Jacob could maybe comment pre op preoperative radiation is really the only way to go. I think for those type of tumors because When you remove the tumor, the bow falls back into place, it becomes extremely difficult to administer radiation in the agreement setting post operatively without high degree of toxicity. But maybe Jacob you can comment on your thoughts there as well. Yeah, 100 agree. You know, first with the new president and I and it really has to be new as of it if it's as event as the doctor characters alluded to. It's really hard to define that area risk and it's all just now. Bow. So that morbidity was way up with unclear benefit. Um And then yeah, it really is a case by case uh discussion. Clearly if it's just a very local recurrence, then it's kind of declared that that's a problem and we would think more aggressively about treating it. Now with multi modal modal therapy, they didn't already receive it. And then also just a comment. Sometimes if they recur they are unrestricted ble depending on where the surgical morbidity is too great in which case then again, if the local only recurrence we would treat it potentially save with definitive radiation with the goal of more durable local control in that area. You know, not certainly not as good as the surgery, but maybe the best option for the patient. The very individualized discussion as as are many of our cases very individualized. That's the importance of the multidisciplinary conference that we have on a regular basis here. So we've we've hit eight o'clock, really wanna appreciate everyone's starting their day with the CMI event again, within the next week, you'll get an email about claiming your CMI credit. Um Thanks again. And if you have further questions about the program, I think you have multiple contacts um uh throughout our team as well. So have a great day. Thanks for joining. Yeah. Thanks everybody sitting up.
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